Project Summary/Abstract The long-term goal of our research program is to understand the functional role of taste receptors (TRs) in pancreatic &#61538;-cells. We have found that a novel class of nutrient-binding G-protein coupled receptors, TRs, is expressed in pancreatic &#61538;-cells. We demonstrate that known TR agonists stimulate insulin secretion in vitro. The scope of this proposal is to demonstrate a role for TRs in nutrient-regulation of insulin secretion in &#61538;-cells, and to understand the signaling pathways involved. In Specific Aim 1 we will investigate the causal relationship between known TR agonists and TRs, with TR siRNA knockdown experiments in &#61538;-cells. The endpoints will be changes in Ca2+-dynamics and insulin secretion. In Specific Aim 2 we will investigate the role of phospholipase C (PLC) and endoplasmic reticulum (ER) Ca2+-release in TR-signaling in &#61538;-cells. The endpoints will be changes in PLC-activity and ER Ca2+-dynamics in response to TR agonists, assayed with fluorescent biosensors. In Specific Aim 3 we will investigate the role of the Transient Receptor Potential Melastatin 5 channel (TRPM5) in TR-signaling in &#61538;-cells. For this purpose we will use TRPM5 mutant mice. The endpoints will be changes in Ca2+-dynamics and insulin secretion in vitro, as well as glucose homeostasis and insulin secretion in vivo. The results of these studies will begin to determine the role of taste receptors and downstream signaling in glucose homeostasis and &#61538;-cell insulin secretion. Insulin secretion is impaired in type 2 diabetes and current treatments are not always sufficient to maintain normo-glycemia. Consequently, it is of importance to find new targets for induction of insulin secretion in diabetes. Here, we propose to investigate a group of potentially druggable targets that in the extension may lead to novel compounds to induce insulin secretion in diabetes.